Hydrazones of pyrazolopyridine carboxylic acids and esters

ABSTRACT

1-R2,3-R3,4-(R4-N(-R5)-N(-R)-),5-(R1-OOC-),6-R6-1H-   PYRAZOLO(3,4-B)PYRIDINE, AND 1-R2,3-R3,4-(Y-C(-X)=N-   N(-R)-),5-(R1-OOC-),6-R6-1H-PYRAZOLO(3,4-B)PYRIDINE   AND SALTS THEREOF WHICH ARE AMTIMICROBIAL AGENTS AND CENTRAL DEPRESSANTS ARE THE SUBJECT OF THIS INVENTION. NEW HYDRAZINES, HYDRAZINES AND HYDRAZONES OF PYRAZOLOPYRIDINE CARBOXYLIC ACIDS AND ESTERS HAVING THE GENERAL FORMULA

United States Patent 3,773,777 HYDRAZONES OF PYRAZOLOPYRIDINE CAR-BOXYLIC ACIDS AND ESTERS Hans Hoehn, Tegernhein, Germany, and MarkChasin, Englishtown, N.J., assignors to E. R. Squibb & Sons, Inc.,Princeton, NJ.

No Drawing. Continuation-impart of application Ser. No. 42,415, June 1,1970, which is a continuation-in-part of application Ser. No. 833,672,June 16, 1969, both now abandoned. This application Dec. 15, 1971, Ser.

Int. Cl. C07d 31/36 US. Cl. 260-2955 B 16 Claims ABSTRACT OF THEDISCLOSURE New hydrazines, hydrazides and hydrazones of pyrazolopyridinecarboxylic acids and esters having the general formula f R X N-N I (I:

\ N-N: Y

Ell-U COORi and R3 COOR;

N Ra Re I 2 and salts thereof which are antimicrobial agents and centraldepressants are the subject of this invention.

This application is a continuation-in-part of application Ser. No.42,415, filed June 1, 1970, now abandoned, which is in turn acontinuation-in-part of Ser. No. 833,672, filed June 16, l969,nowabandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to new hydrazines,hydrazides and hydrazones of pyrazolopyridine carboxylic acids andesters, and salts thereof. The new hydrazines, hydrazides and hydrazoneshave the structural formulas In Formulas I and II, R represents hydrogenor lower alkyl, R represents hydrogen, straight or branched alkyl up to12 carbons, preferably lower alkyl or phenyl-lower alkyl, R representshydrogen, lower alkyl, phenyl, phenyllower alkyl, substitutedphenyl-lower alkyl or cycloalkyllower alkyl, R represents hydrogen,lower alkyl, phenyl or substituted phenyl, R represents hydrogen, loweralkyl,

trihalo(hydroxy)-lower alkyl, trihalo-lower alkyl or phen-- yl, Rrepresents hydrogen or lower alkyl, R represents hydrogen, lower alkyl,phenyl or phenyl-lower alkyl, X

ice

Similar lower alkyl groups are part of the phenyllower alkyl andcycloalkyl-lower alkyl substituents. The substituted phenyl andphenyl-lower alkyl groups include phenyl rings bearing one or twosubstituents, e.g., R R phenyl wherein R and R each is halogen,especially chlorine or bromine, lower alkyl or lower alkoxy. Thus thereare included phenyl, chlorophenyl, e.g., o-, mor pchlorophenyl,bromophenyl, 0-, mor p-tolyl, 2,5-dichlorophenyl, 3,5-dimethylphenyl,3,4-dimethoxyphenyl, benzyl, phenethyl, o-, mor pchlorobenzyl,3,5-dichlorobenzyl, p-methoxyphenyl and the like.

The cycloalkyl groups are cycloaliphatics having three to seven carbons,e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Preferred compounds of Formula I are those in which R is hydrogen, R ishydrogen, alkyl of up to 12 carbon atoms (particularly lower alkyl of upto 8 carbon atoms), or phenyl-lower alkyl, R is hydrogen, lower alkyl orphenyl-lower alkyl, R, is hydrogen or lower alkyl, R, is hydrogen, loweralkyl or phenyl, R is hydrogen or lower alkyl and R is hydrogen or loweralkyl. Preferred compounds of Formula II are those in which R R R and Rhave the meanings just referred to, X is hydrogen, lower alkyl,hydroxy-lower alkyl, phenyl or phenyl-lower alkyl, Y is lower alkyl,phenyl or phenyl-lower alkyl and together X and Y are cyclo-lower alkyl(particularly cyclohexyl). Preferably when either R or R is other thanhydrogen or lower alkyl, the other is hydrogen. The trihalo(hydroxy)lower alkyl group is preferably (l-hydroxy-2,2,2-trichloro)ethyl. Thepreferred halogens are chlorine and bromine, especially the first.

Especially preferred compounds of Formula I are those in which R ishydrogen, R is hydrogen or lower alkyl, especially ethyl, R is hydrogen,ethyl or benzyl, R R and R each is hydrogen or methyl. Especiallypreferred compounds of Formula II are those in which R R and R are thesame as specified for Formula I and X and Y each is lower alkyl,especially methyl or together are cyclohexyl. R is hydrogen or methyl ineach instance.

DETAILED DESCRIPTION The new compounds are formed by the followingseries of reactions. The symbols in the structural formulas have thesame meanings previously described.

A S-aminopyrazole of the formula is produced as described in BritishPatent 1,057,740, pub lished Feb. 8, 1967, by ring closure of analdehyde or ketone hydrazone of the formula (IV) R3 R wherein R is thesame as previously defined and R and R each is hydrogen, lower alkyl,phenyl or phenyl-lower alkyl. The cyclization is effected by heating ata temperature of about to C. in an inert liquid solvent, e.g., analcohol like methanol, ethanol, butanol or the like, preferably in thepresence of a catalyst, e.g., alcoholates like alkali metal alcoholatesparticularly butylates such as sodium butylate.

This S-aminopyrazole is reacted with an alkoxymethylene malonic acidester of the formula Illa 000R;

alkyl-00:0

wherein R represents lower alkyl, e.g., ethoxy methylene 1 malonic-aciddiethyl ester or the like. This may be effected by heating the reactantsat a temperature of the order of 120 C. for several hours, and resultsin a compound of the formula i ll (VII) COORi wherein R is hydrogen andR R R and R correspond respectively to R R R and R of the startingmaterial. This reaction is carried out by heating thepyrazolyl-aminomethylene malonic acid ester of Formula VI in an inertorganic solvent such as diphenyl ether at a temperature of about 230 to260 for several hours while removing, e.g., by distillation, the alcoholR -OH. The product is then separated from the solvent, e.g., byfractional distillation.

Alternatively, instead of cyclizing the malonic acid ethyl estercompound of Formula VI in an inert organic solvent at about 230 to 260as described above, this product also undergoes cyclization by treatmentwith phosphorous oxychlorlde producing directly the intermediate of theformula (V11 Cl COOR Derivatives of Formula VII in which R is hydrogenand R is other than hydrogen may also be prepared by reacting aS-aminopyrazole of Formula III with an acyl malonic acid ethyl ester ofthe formula 3) 0 COORi wherein R is an aromatic or heterocyclic nucleuslike phenyl, naphthyl, furyl, pyridyl, pyrimidyl, pyrazinyl or the like.

This material is processed as described above through the reaction withthe alkoxymethylene malonic acid ester of Formula V and cyclization ofthe roduct of Formula 'VIIor VIIa; 'Ihe CH R group-remains intactthrough these reactions.

At this point, the compound of Formula VII 0r VIIa, having in the1-position the CH R substituent, is oxidized with an oxidizing agentlike selenium dioxide in a high boiling solvent like diethyleneglycoldimethylether at about C. This yields a compound of Formula VII or VIIawherein R is hydrogen.

The free acid, i.e., R is hydrogen, may be obtained from the esterobtained as described. above by hydrolysis, e.g., treatment with aqueoussodium hydroxide solution.

Products of Formula VII wherein R is lower alkyl or phenyl-lower alkylare produced from those wherein R is hydrogen by alkylation, e.g.,treatmentof the latter with an alkylating agent such as an alkyl halideor aralkyl halide like ethyl iodide or benzyl bromide, in an inertorganic solvent such as dimethylformamide in the presence of an alkalimetal carbonate such as potassium carbonate.

Reaction of any of the foregoing products of Formula VII wherein R islower alkyl or phenyl-lower alkyl with at least an equivalent amount ofhydrazine, substituted hydrazine or a salt thereof, e.g., hydrazinehydrate, hydrazine hydrochloride, methylhydrazine, phenylhydrazine orthe like yields a compound of Formula I. The material of Formula VII isdissolved in an inert, preferably dry, organic solvent, e.g., an alcohollike absolute ethanol and the hydrazine is added, preferably alone witha small amount of a metal like zinc chloride. The mixture is heated,e.g., at reflux temperature, for several hours, then the product isisolated.

Alternatively, a compound of Formula'VII wherein R is hydrogen may firstbe converted to its chloro analog (i.e., the hydroxy group is replacedby chlorine) upon treatment with phosphorous oxychloride. The chlorocompound of Formula VIIa, which may also be obtained by cyclization of acompound of Formula VI by means of phosphorous oxychloride, is thentreated with the hydrazine to obtain a product of Formula I.

The hydrazine of Formula I (wherein R and R are both hydrogen) isconverted to the hydrazone of Formula II by reaction with a carbonylcompound, e.g., an aldehyde or ketone, inan inert organic solvent suchas an alcohol. Such carbonyl compounds include, for example,acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde,phenylacetaldehyde, phenylpropionaldehyde, pchlorobenzaldehyde,m-bromobenzaldehyde, 2,5 dichlorobenzaldehyde, p-methoxybenzaldehyde,acetone, dihydroxyacetone, chloral, chloral hydrate, methyl ethylketone, methyl propyl ketone, acetophenone, phenylpropyl ketone,p-chlorophenyl ethyl ketone, cyclopropanone, cyclobutanone,cyclohexanone and the like.

A hydrazine of Formula I wherein R is hydrogen and R is lower alkyl orcycloalkyl may alternatively be obtained by the catalytic reduction ofan appropriately substituted compound of Formula II. V

The bases form salts by reaction with equivalent amounts of the commoninorganic and organic acids. Such salts include the hydrohalides, e.g.,hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate,citrate, oxalate, tartrate, malate, succinate, benzoate, ascorbate,alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g.,benzenesulfonate, etc. It isfrequently convenient to purify or isolatethe product by forming an insoluble salt. The base may be obtained byneutralization and another salt then formed by treatment with theappropriate acid.

The compounds of this invention are useful as antimicrobial agents,e.g., in combatting infections due to organisms such as Trichomonasvaginalis, Staphylococcus aureus or Trychophyton mentagrophytes. Forexample, they may be administered orally to various mammalian species,e.g., mice in an amount of about 5 to 25 mg./kg./ day, preferably in 2to 4 divided doses, in any of the conventional oral dosage forms, ortopically in creams in equivalentamounts. They may be used as surfacedisinfectants. About 0.01 to 1.0% by weight of any of these substancesmay be dispersed on an inert solid or in a liquid such as water andapplied as a dust or spray or incorporated in a soap or other cleaningagent such as a solid or liquid detergent composition. The latter may beused, for example, in general cleaning, in cleaning dairy barns ordairy, food handling or food processing equipment.

The new compounds of this invention are central nervous systemdepressants and may be used as tranquilizers for the relief of anxietyand tension states, for example in mice, rats, dogs and other mammalianspecies, in the same manner as chlordiazepoxide. For this purpose thesecompounds may be incorporated in a conventional dosage form such astablet, capsule, injectable or the like, along with the necessarycarrier material, excipient, lubricant, butter or the like, for oral orparenteral administration in single or divided doses of about 1 to 50mg./kg./day, preferably about 2 to 15 mg./kg., two to four times daily.

The new compounds also increase the intracellular concentration ofadenosine-3',5'-cyclic monophosphate, and thus by the administration ofabout 1 to 100 mg./kg./ day, preferably about 10 to 50 mg./kg. in singleor two to four divided doses in conventional oral or parenteral dosageforms such as those described above may be used to alleviate thesymptoms of asthma.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 1-ethyl-4-hydrazino-lH pyrazol[3,4-b1pyridine-5- carboxylicacid, ethyl ester (a) {[(l-ethyl-S pyrazolyDamino]methylene} malonicacid diethyl ester.--245 g. 1-ethyl-5'-aminopyrazole (2.2 mole) and 476g. ethoxymethylene malonic acid diethyl ester (2.2 mol.) are heated to120 (bath temperature) for 2 hours with stirring. The ethanol formed bythis reaction is removed by means of a water aspirator. Then vacuumdistillation (B.P. 154-160") yields 520 g. (84% of theory) of a quickcrystallizing oil of {[(lethyl-S-pyrazolyl)amino]methylene}malonic aciddiethyl ester, M.P. 5053.

The compound is recrystallized from N-hexane, M.P. 5557.

The hydrochloride salt is formed by treating the above product withdilute ethanolic hydrogen chloride solution.

' (b) 1-ethyl-4-hydroxy-lH-pyrazolo[3,4 b]pyridine-5- carboxylic acidand ethyl ester.-253 g. {[(l-ethyl-S- pyrazolyl)amino]methylene}malonicacid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenylether. The reaction mixture is heated to 235-250 (bath temperature) andallowed to react at this temperature for l-2 hours While the resultingethanol is continuously distilled 01f. The last amount of alcohol isremoved by means of a water aspirator. The diphcnyl ether is separatedby distillation with a fractionating column in vacuo. The1-ethyl-4-hydroxy-lH-pyrazolo-[3,4-b]pyridine 5 carboxylic acid ethylester is obtained at B.P. 115120, yield 195 g.=92% of theory, M.P.85-87". The compound is recrystallized from benezene (90 to 100), M.P.87-89. Hydrolysis of this product with aqueous sodium hydroxide yields1-ethyl-4-hydroxy 1H-pyrazolo[3,4-b-] pyridine-S-carboxylic acid, M.P.201202.

. (c) 4-ethoxy-l-ethyl-1H pyrazolo[3,4-b] pyridine 5 carboxylic acid andethyl ester.In a solution of 259 g. 1.1 mol.)l-ethyl-4-hydroxy-1H-pyrazolo [3,4-b]pyridine- S-carboxylic acid ethylester in 1700 ml. dimethylformamide, 400 g. of well pulverized potassiumcarbonate and 300 g. of ethyl iodide are introduced. The reactionmixture is stirred for 7 hours at 65 and filtered under suction whilehot, from excess potassium carbonate. Upon standing overnight, 165 g. ofl-ethyl-4-ethoxy-lH-pyrazolo- [3,4-b]pyridine-S-carboxylic acid ethylester crystallize out of the solution, M.P. 112-115". After evaporationof the mother liquor, an additional g. are obtained. The total yieldamounts to of theory. The compound is recrystallized from benzene (-100M.P. 113-115.

'By hydrolyzing this product as in part (b)4-ethoxy-lethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid isobtained, M.P. 198-199.

(d) 1-ethyl-4-hydrazino-lH-pyrazolo[3,4 b]pyridine- S-canboxylic acidethyl ester.-3l6 g. of1-ethyl-4-ethoxylH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester(1.2 mol.) are dissolved in 4800 ml. of absolute alcohol. Into thissolution, 72 g. of hydrazine hydrate and 0.4 g. zinc chloride are added.After refluxing for 4 hours, the hot solution is filtered, evaporated todryness in vacuo and the white crystalline residue is crystallized froma benzol-benzene mixture 1:3. There are obtained 250 g. ofl-ethyl-4-hydrazino-1H-pyrazolo[3,4-b] pyridine 5 carboxylic acid ethylester, M.P. 139-140.

The hydrochloride is formed by adding to a solution of 5 grams of theabove obtained hydrazine in 100 ml. of absolute alcohol, with cooling, 5ml. of an alcoholic solution of hydrogen chloride (6.3 N). A whitecrystalline precipitate forms immediately. The mixture is diluted withanhydrous ether, filtered and washed with anhydrous ether. The productis allowed to air-dry overnight.

The l-ethyl-4-hydrazino 1H pyrazolo[3,4-b]pyridine- 5-carboxylic acid,ethyl ester, hydrochloride, is recrystallized from a mixture ofacetonitrile and absolute alcohol, M.P. 2l02l2.

EXAMPLE 2 l-ethyl-4-(2-isopropylidenehydrazino)-lH-pyrazolo[3,4-b]-pyridine-S-carboxylic acid, ethyl ester hydrochloride A solution of 8.4grams of l-ethyl-4-hydrazino-1H- pyrazolo[3,4-b]pyridine-S-carboxylicacid ethyl ester in 100 ml. of acetone is refluxed for one hour. To thecooled solution of the isopropylidene hydrazine, M.P. 9293 there isadded, with cooling, 10 ml. of an alcoholic solution of Hydrogenchloride (6.98 N). A white crystalline precipitate forms immediately.The mixture is diluted with ml. of anhydrous ether to aid in filtering,and the solid filtered, washed with anhydrous ether, and dried at 1 mm.and 110 overnight. The product 1-ethyl-4-(2-isopropylidenehydrazino)-lH-pyrazolo-[3,4 b] pyridine- 5-carboxylic acidethyl ester, hydrochloride, melts at 193- 196", with preliminarysoftening at EXAMPLE 3 1-ethyl-4- 2-isopropylidenehydrazino -1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydrochloride By treating the1-ethyl-4-hydroxy-lH-pyrazolo-[3-4-b] pyridine-S-carboxylic acid ethylester in Example 1b with hydrazine and acetone as in Examples 1d and 2,1-ethyl-4- (2-isopropylidenehydrazino)-lH pyrazolo[3,4b]pyridine-S-carboxylic acid, hydrochloride, is obtained.

EXAMPLE 4 4- (Z-benzylidenehydrazino -l-ethyl-1H-pyrazolo[3 ,4 b]pyridine-S-carboxylic acid, ethyl ester hydrochloride By substituting anequivalent amount of benzaldehyde for the acetone in the procedure ofExample 2, 4-(benzylidenehydrazino)-l-ethyl 1Hpyrazolo[3,4-b1pyridine-5- carboxylic acid, ethyl ester hydrochloride isobtained, M.P. 136-137. Upon saponification, the free acid melts at225-226.

7 EXAMPLE 4-(2-cyclohexylidenehydrazino) 1 ethyl-lH-pyrazolo "'1-'benzyl-.4

" pyrazolo[ 3,4-b]pyridine-S-carboxylic acid, ethyl ester [3,4-b]pyridine 5 carboxylic acid, ethyl ester, hydrochloride By substitutingcyclohexanone for acetone in 'theprocedure of Example 2,4-(2-cyclohexylidene hydrazino) 1 ethyl 1Hpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, M.P. 127, andhydrochloride, M.P. 198199 are obtained. Upon saponification, the freeacid melts at 219.

EXAMPLE 6 1-benzy1-4-(2 isopropylidenehydrazino) 1H pyrazolo [3,4-b]pyridine 5 carboxylic acid, hydrochloride, and 1 benzyl 4 (2benzylidenehydrazino) 1H- pyrazolo[3,4-b] pyridine 5 carboxylic acidhydrochloride By substituting an equivalent amount of l-benzyl-S-aminopyrazole for the l-ethyl-S-aminopyrazole in the procedure ofExample 1, 1 benzyl 4 hydroxy-1H- pyrazolo[3,4-b]pyridine 5 carboxylicacid ethyl ester, M.P. 117-119, and 1 benzyl 4 hydroxy-lH-pyrazolo [3,4b]pyridine 5 carboxylic acid, M.P. 197-198", are obtained.

By treating either of the foregoing compounds with V 8 A PL fi a '-w[(5nitrofurfurylidene)hydrazino] -.;1H-

5 f I. By treating 1 benzyl t ethoxy 1H: pyrazolo [3,4-b]pyridine 5carboxylic acid ethyl" esterifyvith hydrazinehydrate as in Example 1 andthen treating the product With S-nitrofurftiraldehyde accordingto theprocedure of Example 2, the above named compound, M.P. 205-207", isobtained.

EXAMPLE 9 1-ethyl-4[ (5 -nitrofurfury1idene) hydrazino lH -pyra zolo[3,4-b]pyridine-S-carboxylic acid, ethyl ester 7 I hydrazine hydrateaccording to the procedure of Example 1d, 1 benzyl 4 hydrazino 1Hpyrazolo[3,4-b] pyridine 5 carboxylic acid or the ethyl ester isobtained. Then by treating the hydrazine thus obtained with acetone andbenzaldehyde, respectively, according to the procedure of Example 2, theisopropylidene hydrazine hydrochloride and benzylidene hydrazinehydrochloride, respectively, are obtained, as the free carboxylic acidor ethyl ester, respectively.

EXAMPLE 7 1 benzyl 4 (2 phenethylidenehydrazino) 1H- pyrazolo[3,4 b]pyridine 5 carboxylic acid, ethyl ester, hydrochloride By treatment of 1benzyl 4 hydroxy lH-pyrazolo [3,4-b] pyridine 5 carboxylic acid ethylester with ethyl iodide according to the procedure of Example 10, 1-benzyl 4 ethoxy 1H pyrazolo[3,4-b]pyridine-5- carboxylic acid ethylester, M.P. 9496, is obtained. Then by hydrolyzing as in Example 1b, thefree acid is obtained, M.P. 181-182.

By treating the ethyl ester with hydrazine hydrate according to theprocedure of Example 1d, 1-benzyl-4- hydrazino-lH-pyrazolo[3,4b]pyridine-S-carboxylic acid ethyl ester, M.P. 159161, is obtained. Thehydrochloride melts at 215. Then by treating this hydrazine withacetophenone according to the procedure of Example 2, 1benzyl-4-(2-phenethylidenehydrazino)-lH-pyrazolo [3,4b]pyridine 5carboxylic acid, ethyl ester, hydrochloride is Obtained.

Treatment of each of the foregoing compounds of Formula VII withhydrazine hydrate as-in Example 1(d) yields the corresponding hydrazine.Treatment of each of the hydrazines thus obtained with acetone asinExample 2 yields the 4-(isopropylidenehydrazino)-1H-pyrazolo[3,4-b1pyridine carboxylic acid, hydrochlorideyor ester thereof, havingthe same substituents R R and R listed in the second column above.Similarly, by substituting for the acetone an equivalent amount ofbenzaldehyde, pchlorobenzaldehyde, cyclopentanone or acetophenone,respectively, the 4-benzylidene hydrazine,4-(4-chlorobenzylidene)hydrazine, 4-cyclopentylidene hydrazine and 4-(l-phenethylidene)hydrazine and hydrochloride salt, respectively, areobtained Y The following additional compounds are produced by theprocedure of Example 1 i time The following additional compounds areproduced by the procedure of Example 2.

for one hour and is then cooled and filtered. The solid isrecrystallized from 95% ethanol, M.P. 22l222.

1-ethyl-4-(Z-phenylhydrazino)-1H-pyrazo1o [3 ,4-b pyridine-S-carboxylicacid, ethyl ester By substituting an equivalent amount ofphenylhydrazine for the hydrazine hydrate in the procedure of Example1(d),1-ethyl-4-(2-phenylhydrazino)-1H-pyrazolo[3,4-b]pyridine-S-carboxylicacid, ethyl ester, M.P. 176-177", is obtained.

EXAMPLE 32 1 ethyl 4 -[[2 hydroxy l (hydroxymethyl)ethylidene]hydrazino]1H pyrazolo[3,4 b]pyridine carboxylic acid, ethyl ester By substitutingan equivalent amount of dihydroxyacetone for the acetone in theprocedure of Example 2, 1- ethyl 4 [[2 hydroxy 1(hydroxymethyl)ethylidene] hydrazine] 1H pyrazolo[3,4 b] pyridine 5carboxylic acid, ethyl ester, M.P. 175-177", is obtained.

EXAMPLE 3 3 1-ethyl-4- (2-tert.butylhydrazino) -1I-I-pyrazolo[ 3 ,4-b]pyridine-S-carboxylic acid, ethyl ester, hydrochloride By substitutingan equivalent amount of tertiarybutylhydrazine for the hydrazine inExample 1(d) l-ethyl-4- (2-tert.butylhydrazino) 1Hpyrazolo[3,4-b1pyridine-5- carboxylic acid, ethyl ester, hydrochlorideis obtained.

EMMPLE 34 1-benzyl-4-(2,2-diethylhydrazino) -1H-pyrazolo [3 ,4-b]pyridine-S-carboxylic acid, ethyl ester, hydrochloride To 31.6 grams of1-benzyl-4-ethoxy 1H pyrazolo- [3,4-b]pyridine-5-carboxylic acid, ethylester, in 500 ml. of absolute ethanol there are added 9 grams of1,1-diethylhydrazine and 0.2 gram of zinc chloride. The mixture isrefluxed for 5 hours, filtered and concentrated to dryness under reducedpressure. The 1-benzyl-4-(2,2-diethylhydrazino) -*1Hpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, thus obtained iscrystallized from aqueous alcohol.

The compound thus obtained is converted to the hydrochloride bytreatment of an alcoholic solution with an equivalent amount ofalcoholic hydrogen chloride and precipitating the hydrochloride thusformed with anhydrous ether.

EXAMPLE 35 v 4- (Z-acetylhydrazino)-1-ethyl-lH-pyrazolo[3,4-b]

pyridine-S-carboxylic acid, ethyl ester To ml. of acetic anhydride thereis added 3 grams of 4-(2-hydrazino)-1-ethyl 1Hpyrazolo[3,4-b1pyridine-5- carboxylic acid, ethyl ester. The mixture isheated at 100 4-(2,2-diacetylhydrazino)-1-ethyl-lH-pyrazolo-[3,4-b]pyridine-S-carboxylic acid, ethyl ester To 25 ml. of aceticanhydride there are added 3 grams of4-(2-hydrazino)-1-ethyl-1H-pyrazolo[3,4-b1pyridine-5- carboxylic acid,ethyl ester. The mixture is heated at for about one hour and is thencooled and filtered to remove the monoacetylated derivative. Thefiltrate is stirred with 100 ml. of ice water to hydrolyze the unreactedacetic anhydride. The solid which precipitates is filtered and washedwith water. The4-(2,2-diacetylhydrazino)-l-ethyl-1H-pyrazolo[3,4-b]pyridine 5carboxylic acid, ethyl ester is crystallized from hexane, M.P. 1l3114.

EXAMPLE 37 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b] pyridine-S-carboxylicacid ethyl ester (a) 4-chlono-1-ethyl 1H pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester.-A mixture of 23.5 g. of 1- ethyl-4-hydroxy1H pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.1 mol.) andml. of phosphorous oxychloride is refluxed for four hours. Subsequentlythe excess phosphorous oxychloride is removed by distillation in vacuo.As soon as the phosphorous oxychloride has been removed, the oilyresidue solidifies on cooling. It is treated with water and filteredunder suction to obtain4-chloro-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethylester (24.5 g.), M.P. 5560 C. This product is recrystallized fromn-hexane (22.5 g.=87% M.P. 62.

(b) 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b1pyridine-5- carboxylic acidethyl ester.-To a solution of 5.08 g. of 4-chloro-1-ethyl 1Hpyrazolo[3,4-b]pyridine-5carboxylic acid ethyl ester (0.02 mol.) in 50ml. of benzene are added 2.5 g. of hydrazine hydrate (100%) (0.05 mol.).This mixture is stirred at room temperature for 4 days. After this time,the separated hydrazine hydrochloride is filtered under suction and thefiltrate is evaporated 'in vacuo to dryness. The residual product,1-ethyl-4-hydrazinolH-pyrazolo[3,4 b]pyridine-5-carboxylic acid ethylester, is recrystallized from benzene, M.P. 139140.

EXAMPLE 38 l-ethyl-4-phenylhydrazinolH-pyrazolo [3 ,4-b]pyridine-S-carboxylic acid ethyl ester A solution of 25.3 g. of4-chloro-l-ethyl-lH-pyrazolo- [3,4-b]pyridine-5-carboxylic acid ethylester (0.1 mol.) and 21.6 g. of phenylhydrazine (0.2 mol.) in 200 m1. of

benzene is refluxed for four hours. After cooling, the separatedphenylhydrazine hydrochloride is filtered under suction and the filtrateis evaporated in vacuo todryness. The product, 1-ethyl-4-phenylhydrazino1H pyrazolo- [3,4-b]pyridine-5-carboxylic acid ethyl ester isrecrystallized from 96% ethanol, M.P. 176-l77.

EXAMPLE 39 4- (2-cyclohexylidenehydrazino -1H-pyrazolo 3 ,4-b]pyridine-S-carboxylic acid ethyl ester (a) [[[l-(2furyl)methyl-S-pyrazolyl]amino]methylene]malnic acid diethyl ester.163g. of 1-(2-furyl) methyl-S-aminopyrazole (1 mol.) and 216 g. ofethoxymethylene malonic acid diethyl ester (1 mol.) are heated to 130(bath temperature) until the theoretical amount of alcohol is distilledofi. The remaining oil, [[[1-(2- furyl) methyl-S-pyrazolyl] amino]methylene] malonic acid diethyl ester, is recrystallized from methanol,yield 280 g. (84%), M.P. 8486.

(b) 4-hydroxy-1-(2 furyl)methyl-1H-pyrazolo[3,4-b] pyridine-S-carboxylicacid ethyl ester.250 g. of [[[1-(2- furyl) methyl-S-pyrazolyl] amino]methylene] malonic acid diethyl ester (0.75 mol.) are dissolved in 1liter of diphenyl ether and heated to 240 for tWo hours. The ethanolformed is continuously distilled off. The solvent is removed in vacuo.The 4-hydroxy-l-(2-furyl)methyl-1H- pyrazolo[3,4-b]pyridine-S-carboxylicacid ethyl ester remains and is recrystallized from methanol, yield 248g. (86%), M.P. 103-106.

(c) 4-ethoxy-1-(Z-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-S-carboxylicacid ethyl ester.300 g. of 4-hydroxyl-(2-furyl)methyl-1H-pyrazolo[3,4b]pyridine-5-carboxylic acid ethyl ester (1.05 mol.) are dissolved in 1liter of dimethylformamide. 210 g. of potassium carbonate (1.5 mol.) and233 g. of ethyl iodide are added. The mixture is heated at 60 withcontinuous stirring for hours. The excess potassium carbonate isfiltered off. On addition of 500 ml. of water,4-ethoxy-l-(2-furyl)methyllI-I-pyrazolo[3,4-b]pyridine-5-carboxylic acidethyl ester precipitates and is recrystallized from methanol, yield 280g. (85%), M.P. 93-96.

(d) 4-ethoxy-lH-pyrazolo[3,4 b] pyridine carboxylic acid ethylester.31.5 g. of4-ethoxy-1-(2-furyl)methyllH-pyrazolo-[3,4-b]-pyridine-5-carboxylic acidethyl ester (0.1 mol.) and 20 g. of selenium dioxide (0.18 mol.) aresuspended in 100 ml. diethyleneglycol dimethylether. The mixture isheated with stirring at 160 and a few drops of water are added. Thistemperature is maintained for 1.5 hours. After cooling, 100 ml. of waterare added and the mixture is neutralized with a dilute solution ofaqueous ammonia. Yellow crystals are formed, which yield onrecrystallization from methanol 15.8 g. of 4-ethoxy-1H-pyrazolo[3,4-b]pyridine 5 carboxylic acid ethyl ester (67%), M.P. 180.

(e) 4-hydrazino-1H pyrazolo[3,4 b]pyridine 5 carboxylic acid ethylester.--2.35 g. of 4-ethoxy-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acidethyl ester (0.01 mol.) are added with stirring to 10 m1. of hydrazinehydrate. Stirring is continued for min. After this time, 50 ml. of Waterare added and the white precipitate is filtered and recrystallized fromn-butyl alcohol, yield 2 g. of 4-hydrazino-1H pyrazolo[3,4 b]pyridine-5carboxylic acid ethyl ester (90%), M.P. 360.

(f) 4 (2 cyclohexylidenehydrazino) 1H pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester.-4.4 g. of 4-hydrazino-1H-pyrazolo-[3,4-b]pyridine-S-carboxylic acid ethyl ester(0.02 mol.) are suspended in m1. of acetic acid and 2 g. ofcyclohexanone are added with stirring. The mixture is heated to 80 for15 minutes. After this time,4-(2-cyclohexylidenehydrazino)-lH-pyrazolo-[3,4-b] pyridine-S-carboxylicacid ethyl ester precipitates on cooling. The product is recrystallizedfrom acetic acid, yield 4.8 g. (80%), M.P. 265.

.. ,EXAMPLE 40 I 4-hydrazino-1H-pyrazolo 3 ,4b] pyridine-S-carboxylicacid ethyl ester (a) [[[1-(4 picolyl) 5pyrazolyl]amino]methylene]malonic acid diethyl ester.l74 g. ofl-(4-picolyl)-5- aminopyrazole and 216 g. of ethoxymethylene malo-nicacid diethyl ester are heated with stirring at 140, until thetheoretical amount of alcohol has distilled ofii. The reaction mixturecrystallizes on cooling. Recrystallization from ethyl acetate yields 220g. of [[[1-(4-picolyl)-5 pyrazolyl]amino]methylene]malonic acid diethylester (65%), M.P. -97.

(b) 4-hydroxy-l-(4-picolyl) 1H pyrazolo[3,4-b] pyridine-S-carboxylicacid ethyl ester.86 g. of [[[l-(4- picolyl) 5-pyrazolyl]amino]methylene]malonic acid diethyl ester (0.25 mol.) are heated at 240for 15 minutes. The dark oil is cooledand 200 m1. of methanol are added.4 hydroxy 1 (4 picolyl)-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acidethyl ester crystallizes on standing, yield 33 g. (44%), M.P.

(c) 4-hydroxy-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethylester.-3 g. of 4-hydroxy-1'(4-picolyl)-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester (0.01 mol.) are dissolved in 20ml. of acetic acid. 2.2 g. of selenium dioxide (0.02 mol.) and 2-3 dropsof water are added. The mixture is refluxed for 30 minutes and thenfiltered off. 4 hydroxy-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acidethyl ester precipitates on cooling. Recrystallization from acetic acidyields 1.8 g. (87%), M.P. 275.

(d) 4 ethoxy-IH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethylester.4.1 g. of 4-hydroxy-1H-pyrazolo[3,4-b] pyridine-S-carboxylic acidethyl ester (0.02 mol.), 5.6 g. of potassium carbonate (0.04 mol.) and3.5 g. of ethyl iodide (0.022 mol.) are heated in 30 ml. ofdimethylformamide with stirring for 10 hours at 60. After this time, theexcess potassium carbonate is filtered 0E and 30 ml. of water are added.4-ethoxy-1H-pyrazolo[3,4-bJpyridine-S-carboxylic acid ethyl esterprecipitates and is recrystallized from methanol, yield 2 g. (42.5%),M.P. 180.

(e) 4 hydrazino 1H pyrazolo[3,4-b]pyridine 5 carboxylic acid ethylester.The product of part d is treated with hydrazine hydrate in thepresence of zinc chloride as in Example 1d to obtain 4-hydrazino-1H-pyrazolo[3,4 b]pyridine S-carboxylic acid ethyl ester. Uponrecrystallization from acetic acid, the product melts above 320. 7

The following additional products are obtained from the product of parte by the procedure of Examples 2 and 4 respectively: 7

4 (2 isopropylidenehydrazino) 1H-pyrazolo[3,4-b]

pyridine-S-carboxylic acid ethyl ester, M.P. 270, recrystallized fromn-butyl alcohol.

4 (2 benzylidenehydrazino) 1H pyrazolo[3,4-b]

pyridine-S-carboxylic acid ethyl ester, M.P. 270, recrystallized fromn-butyl alcohol.

EXAMPLE 41 1-ethyl-4- (2-isopropylhydrazino)-1I-I-pyrazolo [3,4-b]pyridine-S-carboxylic acid ethyl ester, hydrochloride By substituting anequivalent amount of isopropylhydrazine for the hydrazine in Example1(d), l-ethyl-4-(2- isopropylhydrazino)-1H pyrazolo[3,4 b]pyridine 5carboxylic acid ethyl ester and its hydrochloride are obtained. Thehydrochloride melts at l62164.

EXAMPLE 42 1etliyl-4-(2-isopropylidenehydrazino)-3-methyl-lH-pyrazolo[3,4-b]-pyridine5-carboxylic acid ethyl ester hydrochloride By substituting 2.2moles of 1-ethyl-3-methyl-5-aminopyrazole for thel-ethyl-S-aminopyrazole in Example 1(a) and following the procedure ofthat example and Example 2, 1-ethyl-4-(2-isopropylidenehydrazino)-3-methyl 1H- pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl esterhydrochloride hemihydrate is obtained; it melts with decomposition at197-199, it resolidifies at 209 and remelts at 204-205.

EXAMPLE 43 1 ethyl 4 (2 isopropylidenehydrazino)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, hydrochloride (a)l-ethyl-6-methyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acidethyl ester.51.1 g. of l-ethyl- S-aminopyrazole (0.46 mol.) and 101 g.of acetomalonic acid ethyl ester (0.5 mol.) are added to 224 g. ofpolyphosphorous acid. The mixture is heated with stirring at 120 forthree hours. After this period, the mixture is cooled, diluted with 1000ml. of water and subsequently extracted twice with 300 ml. portions ofchloroform. The chloroform layers are collected, dried over sodiumsulfate and the solvent is distilled off. Recrystallization of theresidue (67 g.) with petroleum ether yields 1-eth'yl-6-methyl-4-hydroxyI 1H pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, M.P. 1l8120.

(b) 4-chl0ro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyri dine-S-carboxylicacid ethyl ester.A mixture of 49.1 g. of 1-ethyl-6-methyl-4-hydroxy 1Hpyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester (0.197 mol.) and250 m1. of phosphorous oxychloride is refluxed for 4 hours. The excessphosphorous oxychloride is removed by vacuum distillation and theresidue is treated with water. The 4-chloro compound (42 g.) is filteredunder suction and recrystallized from n-hexane, M.P. 5456.

(c) 1 ethyl-4-hydrazino-6-methyl-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester.To a solution of 10.7 g. of4-chloro-1-ethyl-6-methyl-lH-pyrazolo[3,4-b] pyridine-S-carboxylic acidethyl ester (0.04 mol.) in 160 ml. of benzene and 80 ml. of pyridine areadded 4 g. of hydrazine hydrate (100%) (0.08 mol.). The mixture isstirred at room temperature for 7 days. After this period theprecipitated hydrazine hydrochloride (2.5 g.) is filtered under suctionand the filtrate is evaporated in vacuo at 30 (bath temperature) todryness. The residue, 1 ethyl4-hydrazino-6-methyl-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethylester is recrystallized from ethyl acetate followed by cooling in therefrigerator. On account of ring closure tendency of this compound, therecrystallization temperature is kept below 40, M.P. 126-128, yield 8.1g. (77%).

(d) 1-ethyl-4-(2-isopropylidene hydrazino)-6-methyl- 1Hpyrazolo[3,4-b]pyridine 5 carboxylic acid ethyl ester.A solution of 5.3g. of 1-ethyl-4-hydrazino-6- methyl 1Hpyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.02 mol.) in 100ml. of acetone is kept at room temperature for 6 days. Upon addition of5 ml. of an alcoholic solution of hydrogen chloride (30 g./ 100 ml.) atroom temperature, the hydrochloride of l-ethyl-4-(2-isopropylidenehydrazino) 6 methyl-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester precipitates. In order toincrease the yield, 100 ml. of anhydrous ether is added to the mixture.Then the hydrochloride is filtered oif under suction, washed withanhydrous ether and dried, yield 6 g. (94.5% M.P. 188-189".Recrystallization from dioxane provides the compound melting at 189-190.

By substituting benzoylmalonic acid ethyl ester and phenylacetomalonicacid ethyl ester, respectively, for the acetomalonic acid ethyl ester inpart a above, 1-ethyl-4- (2 isopropylidenehydrazino) 6phenyl-lH-pyrazolo [3,4-b]pyridine-S-carboxylic acid ethyl esterhydrochloride and1-ethyl-4-(2-isopropylidenehydrazino)-6-benzyllH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester hydrochloride areobtained.

14 EXAMPLE 44 4[2-(2,2,2-trich1oro-1-hydroxyethyl)hydrazino]-1-ethyllH-pyrazolo[3,4-b]pyridine 5 caboxylic acid ethyl ester 2.5 g. of1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethylester (0.01 mol.) and 1.8 g. of chloral hydrate (0.011 mol.) aredissolved in 30 ml. of dimethylformamide and the whole is heated at55-60 (bath temperature) for 6 hours. Subsequently the dimethylformamidesolution is evaporated to dryness in vacuo. The residual oily product,4- [2-(2,2,2-trichloro-1-hydroxyethyl)hydrazino]l-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylic acid ethyl estercrystallizes quickly, yield 3.8 g., upon recrystallization from ethylacetate the product melts at 210-212 (dec.).

EXAMPLE 45 4 (2,2 dimethylhydrazino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester, hydrochloride (a)4-chloro-1-ethyl-1H-pyrazo1o[3,4-b]pyridine-5-carboxylic acid ethylester.A mixture of 12 g. of [[l-ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.043 mol.) and70 ml. of phosphorus oxychloride is refluxed for 10 hours. The excessphosphorous oxychloride is removed in vacuo and the oily residue istreated with 50 ml. of water which causes the oil to become crystalline.The solid material is filtered off under suction and dried in adesiccator; yield 8.5 -g.'=79% of theory. The 4-chloro-l-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esteris recrystallized from n-hexane, M.P. 62.

(b) 4 (2,2 dimethylhydrazino)-1-ethyl-1H-pyrazolo[3,4-bJpyridine-5-carboxylic acid ethyl ester and hydrochloride-To asolution of 25.3 g. of 4-chloro-l-ethyl-1H-pyrazolo[3,4-blpyridine-S-carboxylic acid ethyl ester (0.1 mol.) inml. of anhydrous benzene are added 13.2 g. of N,N-dimethylhydrazine(0.22 mol.). This mixture is stirred at room temperature for 7 days.After this time, the separated product is filtered under suction and thefiltrate is evaporated to dryness in vacuo. The residual compound istreated with 100 ml. of water and the whole stirred for half an hour sothat the product becomes crystalline. 21 g. of4-(2,2-dimethylhydrazino)-1-ethyllH-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester are filtered under suction, then dissolved in ether.Upon drying the ether solution with sodium sulfate and adding of anether solution of hydrogen chloride, the hydrochloride of the hydrazinecompound is formed, M.P. 166- 170; upon recrystallization from ethylacetate, M.P. 174-176.

By neutralization of the foregoing hydrochloride with aqueous ammonia(10%) there is obtained 4-(2,2-dimethylhydrazino)l-ethyllH-pyrazolo[3,4-b]pyridine-5- carboxylic acid ethyl ester, M.P.,1'13-115. Recrystallization from eyclohexane provides a compound meltingat 114-116".

What is claimed is:

1. A compound of the formula wherein R is hydrogen, lower alkyl orphenyl-lower alkyl,

R is hydrogen, lower alkyl, benzyl, chlorobenzyl, phenethyl, C -Ccyclo-alkylmethyl R is hydrogen, C -C alkyl or phenyl, R is hydrogen orC -C alkyl, X is hydrogen, lower alkyl or hydroxy-methyl, Y is loweralkyl, hydroxymethyl and together X and Y are C -C cyclo alkyl orS-nitrofuryl, and pharmaceutically acceptable acid addition saltsthereof.

2. A compound of the'formula COORi wherein R is hydrogen, lower alkyl orphenyl-lower alkyl, R is hydrogen, lower alkyl, benzyl or phenethyl, Ris hydrogen or C -C alkyl, R is hydrogen or methyl, X is hydrogen,methyl or hydroxy-lower alkyl, Y is lower alkyl and together X and Y areC -C cyclo alkyl, and pharmaceutically acceptable acid addition saltsthereof.

3. A compound according to claim 2 wherein R R X and Y each is loweralkyl and R and R each is hydrogen.

4. A compound according to claim 2 wherein R and R each is ethyl, X andY each is methyl and R and R each is hydrogen.

5. The hydrochloride of the compound of claim 4.

6. A compound according to claim 2 wherein R X and Y each is lower alkyland R R and R each is hydrogen.

7. A compound according to claim 2 wherein R is ethyl, X and Y each ismethyl and R R and R each is hydrogen.

8. A compound according to claim 2 wherein R R R X and Y each is loweralkyl and R is hydrogen.

9. A compound according to claim 2 wherein R and R each is ethyl, R ishydrogen, R is methyl and X and Y each is methyl.

10. The hydrochloride of the compound of claim 9.

11. A compound according to claim 2 wherein X and Y together completethe cyclohexyl ring, R is ethyl and R R and R each is hydrogen.

12. A compound according to claim 2 wherein R X and Y each is loweralkyl, R is phenyl-lower alkyl and R and R each is hydrogen.

13. A compound according to claim 2 wherein R is ethyl, R is benzyl, Rand R each is hydrogen and X and Y each is methyl.

14. A compound as in claim 1 wherein R is hydrogen.

15. A compound as in claim 2 wherein R is hydrogen.

16. A compound as in claim 2 wherein R is hydrogen or ethyl, R ishydrogen, ethyl or benzyl, R and R each is hydrogen or methyl, X and Yeach is methyl or together are cyclohexyl.

References Cited UNITED STATES PATENTS 3,629,271 12/1971 Hoehn 260-295.5B

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

26024O G, 295.5 A; 424--266

